Epigenetics - studying how changes in gene expression are caused by external factors - is quickly becoming a revelatory area of health research. And now, researchers have found a new epigenetic mechanism that might play a role in orchestrating the harmful effects of becoming overweight, including diabetes.

The team, led by Prof. Nilesh Samani of the University of Leicester in the UK, have published the results of their study in The Lancet, and they say theirs is one of the largest epigenome-wide studies on the association between adult body mass index (BMI) and DNA methylation.

Explaining this field of study, Prof. Samani says: "Epigenetic changes caused by variation in DNA or environmental factors such as diet, stress, and exposure to chemicals can affect the way genes work (are turned on and off) and may also influence disease susceptibility."

To conduct their study, the researchers analyzed epigenetic changes in DNA regarding BMI, and they examined a process known as DNA methylation.

This process affects specific locations along the DNA called cytosine bases, which are then modified by the inclusion of methyl chemical groups, the team says.

Prof. Samani adds:

"Obesity increases the risk of heart disease, diabetes, cancer and a host of other problems, but we know little about the mechanisms by which obesity increases such risk. Genes only explain part of the story."

Using microarray technology to measure methylation levels at over 350,000 sites of the genome, the team assessed blood DNA samples from over 400 individuals of European origin. They then identified five sites where the methylation level correlated with BMI.

Once they landed on these findings, the researchers then tested them in two other sets of individuals of European ancestry.

Their results confirmed significant association with three methylation sites located near the HIF3A gene, which is a gene that codes a protein that senses oxygen levels in cells and "tries to compensate for low levels by affecting the expression of a large number of other genes," Prof. Samani explains.

Methylation of HIF3A 'increasingly altered with obesity'

Because the strong associations were with three methylation sites located near the HIF3A gene, the team says it suggests this is an authentic modification of DNA related to changes in weight.

They found that for every 10% increase in methylation at the most significant site, BMI increased by 3-6%, which is the equivalent to about 0.98 kg/m2 for a person from the study with an average BMI of 27 kg/m2.

Additionally, while the researchers found that changes in methylation at sites in the HIF3A gene are linked with BMI in DNA from fat tissue - which is directly involved in obesity - they did not find this link in skin DNA.

They also note that their findings showed changes in methylation of HIF3A were likely to be a result of increased weight, rather than a cause.

But Prof. Samani says the link they found between HIF3A methylation and BMI was "quite unexpected," adding:

"To find that the methylation of HIF3A is increasingly altered as someone becomes more obese is remarkable and raises the possibility that HIF may also be involved in mediating some of the deleterious effects of becoming overweight."

Although he says further studies are needed to fully understand this process, he adds that their findings could pave the way to new treatments for how obesity affects the body.

"At a more general level," he adds, "our study shows that investigating epigenetic changes in DNA may reveal new mechanisms involved in common diseases."

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